title: Apurinic/Apyrimidinic endonuclease 1 regulates inflammatory response in macrophages.
abstract: The multi-functional apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) DNA repair and redox signaling protein has been shown to have a role in cancer growth and survival, however, little has been investigated concerning its role in inflammation. In this study, an APE1 redox-specific inhibitor (E3330) was used in lypopolysaccharide (LPS)-stimulated macrophages (RAW264.7). E3330 clearly suppressed secretion of inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL-6) and IL-12 and inflammatory mediators nitric oxide (NO) as well as prostaglandin E(2) (PGE(2)) from the LPS-stimulated RAW264.7 cells. These data were supported by the down-regulation of the LPS-dependent expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) genes in the RAW264.7 cells. The effects of E3330 were mediated by the inhibition of transcription factors nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) in the LPS-stimulated macrophages, both known targets of APE1. In conclusion, pharmacological inhibition of APE1 by E3330 suppresses inflammatory response in activated macrophages and can be considered as a novel therapeutic strategy for the inhibition of tumor-associated macrophages.
authors.affiliation: Cancer Research Laboratory, Methodist Research Institute, Indiana University Health, 1800 N Capitol Ave, E504, Indianapolis, IN 46202, USA.
authors.forename: Andrej
authors.initials: A
authors.lastname: Jedinak
authors.forename: Shailesh
authors.initials: S
authors.lastname: Dudhgaonkar
authors.forename: Mark R
authors.initials: MR
authors.lastname: Kelley
authors.forename: Daniel
authors.initials: D
authors.lastname: Sliva
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016227:Benzoquinones / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D015232:Dinoprostone / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D010084:Oxidation-Reduction; D011422:Propionates / Q000494:pharmacology; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016227:Benzoquinones; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011422:Propionates; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C075569:E 3330; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D015232:Dinoprostone